Selective class I phosphoinositide 3-kinase inhibitors: optimization of a series of pyridyltriazines leading to the identification of a clinical candidate, AMG 511 PMID: 22897589

Target-related Cytokines

2026-09-23

Selective class I phosphoinositide 3-kinase inhibitors: optimization of a series of pyridyltriazines leading to the identification of a clinical candidate, AMG 511

J Med Chem. 2012 Sep 13;55(17):7796-816. doi: 10.1021/jm300846z.

Mark H Norman ¹ , Kristin L Andrews , Yunxin Y Bo , Shon K Booker , Sean Caenepeel , Victor J Cee , Noel D D'Angelo , Daniel J Freeman , Bradley J Herberich , Fang-Tsao Hong , Claire L M Jackson , Jian Jiang , Brian A Lanman , Longbin Liu , John D McCarter , Erin L Mullady , Nobuko Nishimura , Liping H Pettus , Anthony B Reed , Tisha San Miguel , Adrian L Smith , Markian M Stec , Seifu Tadesse , Andrew Tasker , Divesh Aidasani , Xiaochun Zhu , Raju Subramanian , Nuria A Tamayo , Ling Wang , Douglas A Whittington , Bin Wu , Tian Wu , Ryan P Wurz , Kevin Yang , Leeanne Zalameda , Nancy Zhang , Paul E Hughes

Affiliations

Abstract

The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential Cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma Glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511.